Journal of Gastroenterology and Hepatology

Free Access

Hypoxia and hepatocellular carcinoma: The therapeutic target for hepatocellular carcinoma

Corresponding Author

Department of Integrative Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin,

Dr Xiong‐Zhi Wu, Department of Integrative Oncology, Tianjin Medical University Cancer Institute and Hospital, Ti‐Yuan‐Bei, Huan‐Hu‐Xi Road, He‐Xi District, Tianjin 300060, China. Email:

ilwxz@163.com

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Guang‐Ru Xie

Department of Integrative Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin,

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Dan Chen

Department of Biophysics, School of Basic Medical Sciences, Peking University, Beijing, China

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Xiong‐Zhi Wu

Corresponding Author

Department of Integrative Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin,

Dr Xiong‐Zhi Wu, Department of Integrative Oncology, Tianjin Medical University Cancer Institute and Hospital, Ti‐Yuan‐Bei, Huan‐Hu‐Xi Road, He‐Xi District, Tianjin 300060, China. Email:

ilwxz@163.com

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Guang‐Ru Xie

Department of Integrative Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin,

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Dan Chen

Department of Biophysics, School of Basic Medical Sciences, Peking University, Beijing, China

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First published: 06 August 2007

https://doi.org/10.1111/j.1440-1746.2007.04997.x

Cited by: 91

Abstract

Hypoxia enhances proliferation, angiogenesis, metastasis, chemoresistance, and radioresistance of hepatocellular carcinoma (HCC); suppresses differentiation and apoptosis of HCC; and consequently leads to resistance of transarterial embolization (with or without chemotherapy). Because transarterial embolization contributes to angiogenesis via inducing hypoxia, therapy combined with transarterial embolization and antiangiogenic therapy provides a new strategy for the treatment of HCC. Unfortunately, hypoxia leads to the escape of HCC cells from transarterial embolization and antiangiogenic therapy. Thus combined therapy that induces and targets hypoxia may be of benefit to HCC patients. Because angiogenesis plays an important role in recurrence of HCC after resection, antiangiogenic therapy is beneficial to HCC patients following surgical resection of the tumor.

Introduction

Hepatocellular carcinoma (HCC) is the fifth most common malignant disorder and causes nearly one million deaths each year worldwide. HCC is developed through cirrhosis induced by chronic liver injury. This chronic injury causes fibrogenesis to demolish the normal liver blood system. Damage to the liver blood system leads to the shortage of blood circulation in the liver and consequently leads to hypoxia. Moreover, the high proliferation of tumor cells also induces local hypoxia inside HCC.

Hypoxia induced factor‐1 (HIF‐1) is the major transcription factor that is specifically activated during hypoxia. This transcription factor is composed of two subunits: HIF‐1α and aryl hydrocarbon receptor nuclear translocator (ARNT). ARNT is constitutively expressed, whereas HIF‐1α is targeted to proteasome degradation by ubiquitination during normoxia. In hypoxia, HIF‐1α is stabilized and translocates to the nucleus, where it binds to ARNT. The active HIF‐1 induces the expression of various genes whose products control angiogenesis, glucose metabolism, survival, and tumor spread (Fig. 1).1, 2 When HCC displays the features of hypoxia, it is critical to comprehend the double roles of hypoxia in the therapy of HCC.

**Figure 1**
Open in figure viewer PowerPoint

HIF‐1 is the major transcription factor that is specifically activated during hypoxia. This transcription factor is composed of two subunits: HIF‐1α and ARNT (HIF‐1β). ARNT is constitutively expressed, whereas HIF‐1α is targeted to proteasome degradation by ubiquitination during normoxia. In hypoxia, HIF‐1α is stabilized and translocates to the nucleus, where it binds to ARNT. The active HIF‐1 induces expression of various genes whose products control angiogenesis. HIF‐1: Hypoxia induced factor‐1, ARNT: aryl hydrocarbon receptor nuclear translocator, HREs: hypoxia response elements.

Caption
HIF‐1 is the major transcription factor that is specifically activated during hypoxia. This transcription factor is composed of two subunits: HIF‐1α and ARNT (HIF‐1β). ARNT is constitutively expressed, whereas HIF‐1α is targeted to proteasome degradation by ubiquitination during normoxia. In hypoxia, HIF‐1α is stabilized and translocates to the nucleus, where it binds to ARNT. The active HIF‐1 induces expression of various genes whose products control angiogenesis. HIF‐1: Hypoxia induced factor‐1, ARNT: aryl hydrocarbon receptor nuclear translocator, HREs: hypoxia response elements.

Hypoxia and hepatocarcinogenesis

Generally, hypoxia suppresses the proliferation of cells. Human mammary epithelial cells (HMEC), normal fibroblasts cells (Hs68 and WI38), cervical carcinoma cells (HeLa), and breast carcinoma cells (HTB‐30) are arrested in G (1)/S in response to severe hypoxia. However, Hep3B HCC cells do not exhibit orderly G (1)/S arrest in response to severe hypoxia.3 On the contrary, hypoxia stimulates the growth of HCC via inducing the expression of hexokinase II, an enzyme taking part in the salvage pathway of generating ATP.4 Hypoxia also up‐regulates insulin‐like growth factor‐2 and thus stimulates the growth of HCC cells.5

Besides the role of adaptation to hypoxia, recent data have described the possible role of HIF‐1 in modulating apoptosis of HCC.6-9 HIF‐1 protects cells against apoptosis under hypoxia by over‐expressing myeloid cell factor‐1, an antiapoptotic protein delaying or blocking the apoptosis of HCC.6 Moreover, hypoxia enhances the expression of vascular endothelia growth factor (VEGF), which decreases the ratio of Bax/Bcl‐2, and consequently leads to apoptosis blocking of HCC.10 Hypoxia induces the expression of cyclic AMP‐responsive element binding protein, a transcription factor which is activated by multiple extracellular signals and modulates cellular response by regulating the expression of a multitude of genes to control growth, support angiogenesis, and render apoptosis resistance.11

The molecular mechanisms underlying the phenotypic heterogeneity are very complex with genetic, epigenetic, and environmental components. Hypoxia greatly influences cellular phenotypes by altering the expression of specific genes.12 The development of a complex organism relies on the precise and special expression of its genome in many different cell types. Hepatic nuclear factor −4 is a key element in the liver‐specific transcriptional regulation of genes.13 Hypoxic stress triggers a cascade of events that inhibit the transactivation potential of hepatic nuclear factor −4 in HepG2 cell, and consequently leads to dedifferentiation.14

Taken together, hypoxia enhances the proliferation of HCC, suppresses the differentiation and apoptosis of HCC, and consequently leads to tumor malignancy. The hypothesis is that because of long‐term hypoxia, HCC cells develop the ability to survive and proliferate in a hypoxia microenvironment. It is important to understand how tumor growth occurs in such challenging environmental conditions.

Hypoxia and angiogenesis

HCC is a hypervascular tumor and angiogenesis plays an important role in its progression.15 Hypoxia stimulates angiogenesis to support tumor growth by inducing the expression of angiogenic factors, such as insulin‐like growth factor II and VEGF.5, 16 HIF‐1 occurring in the hypoxic regions of the tumor plays an important role in VEGF expression, angiogenesis, and tumor growth.17 Furthermore, hypoxia induces the expression of Rac. Rac and Id‐1 (inhibitor of differentiation/DNA synthesis) increase the stabilization of HIF‐1α, resulting in the up‐regulation of VEGF.18, 19 Along with the expression of HIF‐1α and VEGF, the expression of tumor suppressors von Hippel‐Lindau and p53 is down‐regulated by hypoxia.20 Thus hypoxia is a major cause of hypervasculature in HCC.21 The disease‐free survival time of patients with high HIF‐1α expression is significantly shorter than that of the low expression group.22 Therefore, the role of hypoxia‐regulatory factors could provide new insights into the treatment of HCC.

Recently, the development of hypoxia target drugs has evoked an extensive interest in cancer therapy.23 HIF‐1α is a new target for the antiangiogenic therapy of HCC. Curcumin (a natural compound isolated from the commonly used spice turmeric), green tea extract and its major component (–)‐epigallocatechin‐3‐gallate, and resveratrol (a natural product commonly found in grapes and various other fruits), 3‐(5′‐hydroxymethyl‐2′‐furyl)‐1‐benzyl indazole (YC‐1), TX‐402 (a quinoxaline noxide), vitexin (a natural flavonoid compound identified as apigenin‐8‐C‐b‐D‐glucopyranoside), CK2α siRNA, and rapamycin significantly inhibit hypoxia‐induced angiogenesis via down‐regulating the expression of HIF‐1 and VEGF in HepG2 cells (Table 1).24-32

Table 1. Agents targeting hypoxia induced factor‐1α in hepatocellular carcinoma

Agent	Resource	References
Curcumin	Isolated from turmeric	24, 25
(–)‐epigallocatechin‐3‐gallate	Extract from green tea	26
Resveratrol	Commonly found in various fruits, such as grapes	27
YC‐1	Chemical synthesis (3‐(5′‐hydroxymethyl‐2′‐furyl)‐1‐benzyl indazole)	28
Rapamycin	Isolated from Streptomyces hygroscopicus	29
TX‐402	Chemical synthesis (a quinoxaline Noxide)	30
Vitexin	A natural flavonoid compound identified as apigenin‐8‐C‐b‐D‐glucopyranoside	31
CK2α siRNA	Chemical synthesis	32

Hypoxia and metastasis

Hypoxia is clinically associated with metastasis and poor outcomes, although the underlying processes remain unclear.33 Hypoxic stress accelerates the invasion of hepatoma by up‐regulating ETS‐1 and the matrix metalloproteinases family by the HIF‐1α‐independent pathway.30, 34 The expression of HIF‐1α is correlated with VEGF.35 Rapamycin and vitexin inhibit the metastasis of HCC by down‐regulating the expression of VEGF and HIF‐1α.29, 31

The plasma VEGF level after transcatheter arterial chemoembolization (TACE) was increased, and the plasma VEGF levels had a tendency to increase in patients with heterogeneous uptake of portal vein thrombosis. Follow‐up for six months showed metastatic foci in 70% patients with increased plasma VEGF, but none of the patients with decreased plasma VEGF developed metastasis.36 Thus increased plasma VEGF expression may be associated with the development of metastasis in HCC after TACE. Moreover, increased plasma insulin‐like growth factor II level after TACE, which is common in patients with large‐sized tumors and high serum AFP levels, appears to be associated with the metastasis after TACE.37

Hypoxia, chemoresistance, and radioresistance

Hypoxia in tumors is generally associated with chemoresistance and radioresistance.38, 39 Apoptosis of HIF‐1α‐transfected cells is inhibited when they are exposed to 5‐Fu.40 Hypoxia protects HepG2 cells against etoposide‐induced apoptosis by inducing the expression of AP‐1.41 Moreover, the expression of multidrug resistance–related genes mdr1, multidrug resistance transporter P‐glycoprotein, and lung resistance protein in HCC is under the control of HIF‐1.40, 42 Thus, hypoxia induces multidrug resistance in HCC via hypoxia‐elicited multidrug resistance related protein. Furthermore, hypoxia and HIF‐1 promote the expression of genes which increase radioresistance in HCC.43

Therapeutic strategy based on antihypoxia

High serum VEGF levels have been shown to predict poor response and survival rates of patients with inoperable HCC who undergo TACE treatment.44 VEGF antisense oligodeoxynucleotides mixed with lipiodol embolization is better for inhibiting HCC growth, VEGF expression, and MVD than lipiodol alone.45 TNP‐470, an antiangiogenic agent, is more effective when combined with hepatic artery ligation.46 Thus TACE or TAE therapy combined with antiangiogenic therapy provides a new strategy for the treatment of HCC.

Besides inducing chemoresistance, hypoxia leads to the escape of HCC cells from transarterial embolization (TAE) and antiangiogenic therapy. The proliferate activity of HCC cells is increased by ischaemic necrosis induced by TAE.47 Escape of HCC cells from anoxic injury induced by TAE is enhanced by inducing proteins that provide resistance to apoptosis, such as Bcl‐2 and VEGF.48 Because inducing hypoxia has the potential effect of promoting the malignancy of escape cancer cells after TAE, TACE, or antiangiogenic therapy, antihypoxia, such as inhibiting HIF‐1a activity, provides an important strategy for HCC patients. We advocate that a combined therapy of agent‐inducing hypoxia with antihypoxia may be of benefit to HCC patients.

Furthermore, angiogenesis plays an important role in the recurrence of HCC after resection. The expression of VEGF and ang‐2 is correlated with MVD, and strong ang‐2 expression and/or high nuclear expression of HIF‐1α are significant predictive factors for recurrence after curative resection in HCC patients.49 Thus antiangiogenic therapy may be of benefit to patients with HCC following surgical resection of the tumor. Generally, sulfated polysaccharides and sulfated oligosaccharides have the property of inhibiting angiogenesis.50 Phosphomannopentaose sulfate (PI‐88), a mixture of sulfated oligosaccharides, has the important property of inhibiting angiogenesis and heparanase activity.51 A phase II clinical trial of PI‐88 for the treatment of patients with HCC following surgical resection showed that PI‐88 increased time to tumor recurrence by 76% in patients with HCC following resection.52 Recently, our group isolated sulfated polysaccharides from the Gekko swinhonis Güenther.53 Our research has shown that sulfated polysaccharides in the gekko suppress the secretion of IL‐8, an angiogenic factor, by HCC (unpublished data; to be collated in 2007). Gekko sulfated polysaccharides do not dramatically suppress the livability and proliferation of normal liver cells. Thus treatment with gekko sulfated polysaccharides may potentially benefit patients with HCC following surgical resection.53

Conclusion

The liver is one of the organs in which hypoxia helps to regulate gene expression under normal physiological conditions, as well as diseases such as cirrhosis and cancer. Hypoxia enhances proliferation, angiogenesis, metastasis, chemoresistance, and radioresistance of HCC; suppresses differentiation and apoptosis of HCC; and consequently leads to tumor malignancy. It is important to understand how tumor growth occurs in such challenging environmental conditions.

Because HCC is a typical hypervascular tumor, therapy aimed at tumor vessels to induce hypoxia is expected to be of benefit for some patients who are only suited to palliative treatment. TACE and TAE contribute to the angiogenesis of HCC through inducing hypoxia. The combined therapy of TACE or TAE with antiangiogenic therapy provides a new strategy for the treatment of HCC. However, hypoxia leads to the escape of HCC cells from TAE and antiangiogenic therapy. We advocate that a combined therapy of agent‐inducing hypoxia with agent‐targeting hypoxia may be of benefit to HCC patients. Because angiogenesis plays an important role in the recurrence of HCC after resection, antiangiogenic therapy may be of benefit to patients with HCC following surgical resection of the tumor.

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Volume22, Issue8

August 2007

Pages 1178-1182

Journal of Gastroenterology and Hepatology

Hypoxia and hepatocellular carcinoma: The therapeutic target for hepatocellular carcinoma

Abstract

Introduction

Hypoxia and hepatocarcinogenesis

Hypoxia and angiogenesis

Hypoxia and metastasis

Hypoxia, chemoresistance, and radioresistance

Therapeutic strategy based on antihypoxia

Conclusion

Number of times cited: 91

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Journal of Gastroenterology and Hepatology

Hypoxia and hepatocellular carcinoma: The therapeutic target for hepatocellular carcinoma

Abstract

Introduction

Hypoxia and hepatocarcinogenesis

Hypoxia and angiogenesis

Hypoxia and metastasis

Hypoxia, chemoresistance, and radioresistance

Therapeutic strategy based on antihypoxia

Conclusion

Number of times cited: 91

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